Basically substituted o-arylamino-benzamides



Patented Mar. 9, 1954 UNITED STATES PATENT osFIcE 'BASICALLY SUBSTITUT-ED ;o-ARLAMINO- BENZAMIDES Carl Peter Krimmcl, Mundelin, IIL, assignor to G. D. Searle & '00., ChicagoQIlL, a corporation of Illinois No Drawing. Application July 2, 1952, Serial No. 296,941

and the non-toxic salts thereof, wherein Ar is an aryl radical, Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms, and NRR is either a lower dialkylamino radical or a nitrogen containing heterocyclic radical attached through a nitrogen in the heterocycle to the radical Alk.

In the above structural formula Ar is a lower aryl radical and, preferably, a monocyclic aromatic hydrocarbon radical such as phenyl, tolyl, xylyl, ethylphenyl, or cumyl. The radical Alk is a straight-chained or branch-chained hydrocarbon radical such as ethylene, propylene, butylene, amylene, or a polymethylene radical such as trimethylene or octamethylene. The radicals .R and R are lower alkyl radicals of the straightchained or branch-chained type such as methyl, ethyl, propyl, butyl, amyl, and hexyl. The radicals R and R can also be combined to form a lower alkylene radical containing 4 to 7 carbon atoms, 4 to of which are in nuclear position as in the case of pyrrolidino, piperidino, 2,5-dimethylpyrrolidino, and 2,6-1upetidino radicals. They may also be combined as an ethyleneoxyethylene radical, ethylenethiaethylene radical, or ethyleneaminoethylene radical as in the cases of the morpholino, thiamorphalino and piperazino radicals.

The bases described herein form salts which are non-toxic in therapeutic dosage with a variety of inorganic and strong organic acids such as phosphoric, hydrochloric, hydrobromic, hydriodic, sulfamic, acetic, maleic, malic, succinic, tartaric, citric, ascorbic gluconic, benzoic, cinnamic, or related acids. They also form quaternary ammonium salts with a variety of organic esters of sulfuric, hydrohalic, and aromatic sulfonic acids. Among such esters are methyl chloride, bromide, and iodide; the ethyl halides, propyl halides, butyl halides, isobutyl halides, benzyl halides, phenethyl halides, naphthylmethyl halides, dimethyl sulfate, methyl benzenesulfonate, ethyl toluenesulfonate, ethylene chlorohydrin, ethylene bromohydrin, the propylene halohydrins, 'allyl chloride, methallyl bromide, and crotyl bromide.

11 Claims. (CIQZBO- -SBS) .'Ihe new group of amides described herein offers valuable intermediates in organic synthesis. These amides have shown valuable cardiovascular and specifically blood pressure reducing properties. Th acid addition salts are diuretics and the quaternary ammonium salts have been found to be potent ganglion blocking agents.

The examples below illustrate my invention in further detail. However, they are not'to be construed as limiting it in spirit or in scope. In these examples quantities of materials are given in parts by weight, temperatures in degrees Centigrade (C.), and pressures in millimeters (mm) of mercury.

EXAMPLE '1 N- (fl-diethylaminoethyl) -o-anilinobenzamide A mixture of 426 parts of N-phenylanthranilic acid, 1100 parts of anhydrous ethyl ether, and 272 parts of thionylchloride is heated in a water bath at 40 C. for one hour. The ether is then removed under vacuum at room temperature and the crude a'cid chloride residue is used in the reactions with the dialkylaminoalkylamines.

To a solution of the above residue in 1600 parts of acetone, 232 parts of fi-diethyl'aminoethylamine are added by dropwise addition, with stirring. After the addition the reaction mixture is refluxed on the steam bath for an hour. The acetone is removed under vacuum and the residue is dissolved in water and ether extracted. The aqueous phase is made alkaline with potassium carbonate and ether extracted. The ether extract is dried over anhydrous potassium carbonate, ether stripped, and vacuum distilled. The N (B-di'ethylaminoethyl)-o-anilinobenzamid is a viscous, orange oil boiling at approximately 221-227 C. and 0.5 mm. pressure.

Toa solution "of 280 parts of the base in 11,000 parts of anhydrous ethyl ether, one equivalent of a 25% solution of hydrogen chloride in isopropanol is added. A brown gum separates which, after three recrystallizations from butanone, is converted to a tan-colored crystalline powder melting at 163-164" C. This salt has the structural formula 3 EXAMPLE 2 [i- (o-anz'linobenzamidoethyl) triethylammomum bromide A mixture of 110 parts of N-(B-diethylaminoethyl) -o-anilinobenzamide, 76 parts of ethyl bromide, and 1600 parts of butanone is sealed in a pressure bottle and heated in the steam bath for 3 hours. Observing the usual precautions, the pressure bottle is cooled and opened. A heavy syrup is separated from the reaction mixture by dilution with anhydrous ethyl ether. The syrup is washed by ether decantation, taken up in acetone, and crystallized by cooling in the refrigerator. Two recrystallizations from aceton and vacuum drying yield pale yellow crystals of the p-(o-anilinobenzamidoethyl)triethylammonium bromide which are too hygroscopic for the determination of a sharp melting point. The salt has the structural formula EXAMPLE 3 N y-dimethylaminopropyl) -o -ahilinobenzamide To the acid chloride residue prepared from 41 parts of N-phenylanthranilic acid, a solution of 20 parts of 'y-dimethylaminopropylamine in 100 parts of acetone is added slowly with stirring. After heating at reflux temperature for an hour the acetone is distilled off under vacuum and the residue is dissolved in water. The aqueous extract is Washed with ether, rendered alkaline by addition of potassium carbonate, and ether extracted. This ether extract is dried over anhydrous potassium carbonate, solvent stripped, and vacuum distilled to yield the N-(- -dimethyl-. aminopropyl)-o-anilinobenzamide as a viscous yellow oil boiling at about 223-230 C. and 0.3 mm. pressure.

To a solution of 9.5 parts of the base in 1400 parts of anhydrous ethyl ether is added one equivalent of a 25% solution of hydrogen chloride in isopropanol. The resultant granular pink precipitate is filtered, ether washed, and vacuum dried under an infrared lamp. Drying transforms the precipitate to a red gum. The latter is taken up to 40 parts of butanone from which it rapidly crystallizes. After one recrystallization from butanone a white, non-hygroscopic crystalline powder is obtained which melts at 133-135 C. This salt has the structural formula acetone.

4 EXAMPLE 4 N- ('y-diethylaminopropyl) -o-anilinobenzamide 1 To the acid chloride residue prepared from 318 parts of N-phenylanthranilic acid is added, with stirring, a solution of 195 parts of 'y-diethylaminopropylamine in 1000 parts of acetone. The addition causes refluxing which is maintained for one hour by heating on the steam bath. The acetone is removed under vacuum and the residue is dissolved in water and ether washed. The aqueous phase is made alkaline with potassium carbonate and ether extracted. This ether extract is dried over anhydrous potassium carbonate, ether stripped and vacuum distilled. The N- ('y-diethylaminopropyl) -o-anilinobenzamide is a viscous yellow oil boiling at about 220-230 C. and 0.3 mm. pressure.

To a solution of 60 parts of the base in 14,000 parts of anhydrous ethyl ether, an equivalent of a 25% solution of hydrogen chloride in isopropanol is added. The hydrochloride precipitates as a tacky deposit which becomes a crystalline powder on standing and scratching. Filtration and vacuum drying under an infrared lamp yield a cream colored, non-hygroscopic powder, melting at about 97-103" C. The salt has the structural formula EXAMPLE 5 N-(e dimethylaminopropyl) o (mm xylyl) aminobenzamide The acid chloride residue prepared from '12 parts of N-(m,pxylyl)anthranilic acid is treated by dropwise addition with a solution of 31 parts of 5-dimethylaminopropylamine in 150 parts of After heating at reflux temperature for 90 minutes the solvent is removed under vacuum. The residue is dissolved in water and the resulting solution washed with ether, rendered alkaline by addition of potassium carbonate, and ether extracted. This extract is dried EXAMPLE 6 N-(w-diethylaminopentyl) o anilznobenzamz'de A solution of phenylanthranilic acid chloride. prepared from parts of the acid in 500 parts of acetone, is treated with stirring by the gradual I claim: 1. A member of the class consisting of the compounds of the structural formula and the salts of the structural formula Air-NH wherein Ar is a monocyclic hydrocarbon radical containing 6 to 9 carbon atoms, Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least 2 carbon atoms and X is a non-toxic anion.

2. A compound of the structural formula wherein Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms.

3. A compound of the structural formula wherein Alk is a lower alkylene radical separatmg the two nitrogen atoms attached thereto by at least two carbon atoms.

4. A compound of the structural formula 5. A compound of the structural formula wherein Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms.

6. A compound of the structural formula 7. A compound of the structural formula 8. A compound of the structural formula 9. A salt of the structural formula wherein Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms, and X is a nontoxic anion.

10. A salt of the structural formula C ONH-A1k-N (lower alkyl);

halogen wherein Alk is a lower alkylene radical separating the two nitrogen atoms attached thereto by at least two carbon atoms.

11. A salt of the structural formula CARL PETER KRIMMEL.

References Cited in the file of this patent UNITED STATES PATENTS Name Date Eisleb Mar. 9, 1937 OTHER REFERENCES Bachman et al.: J. Am. Chem. Soc., vol. 68 (1946), page 2112.

Number 

1. A MEMBER OF THE CLASS CONSISTING OF THE COMPOUNDS OF THE STRUCTURAL FORMULA 